Calcium carbonate granulation

ABSTRACT

Highly compactable granulations and methods for preparing highly compactable granulations are disclosed. More particularly, highly compactable calcium carbonate granulations are disclosed. The granulations comprise powdered materials such as calcium carbonate that have small median particle sizes. The disclosed granulations are useful in pharmaceutical and nutraceutical tableting and provide smaller tablet sizes upon compression than previously available.

This application is a divisional application of U.S. application Ser.No. 10/631,923, filed Jul. 31, 2003, the entire contents of which arehereby incorporated by reference.

FIELD OF INVENTION

The present invention relates generally to highly compactablegranulations and methods for preparing the same. More particularly, thepresent invention relates to highly compactable calcium carbonategranulations for use in pharmaceutical and nutraceutical tableting.

BACKGROUND OF THE INVENTION

Calcium is an essential nutrient and the most abundant mineral in thehuman body. Calcium plays a vital role in building healthy teeth andbones, blood clotting, muscle contraction, and nerve function. Inaddition to these benefits, it has recently been suggested that calciumreduces the risk of recurrence of colon polyps. see Baron J. A. et al.New England Journal of Medicine 1999; 340: 101-107. Most notably,calcium reduces the risk of bone loss caused by osteoporosis in both menand women. Despite these advantages, it has been estimated that half ofall Americans do not consume sufficient amounts of calcium. Moretroubling, 80% of women, the group at highest risk for developingosteoporosis, do not consume enough calcium.

This deficiency is due in part to the large daily intake of calcium thatis suggested by physicians. The United States Recommended DailyAllowance (“USRDA”) of calcium for adults is 800 to 1,400 mg. TheNational Academy of Sciences, Institute of Medicine recommends calciumintakes of 1,200 mg per day for people over 50 years of age and 1,300 mgper day for people under 19 years of age. Not surprisingly, physiciansrecommend calcium supplements more than any other dietary supplement.

Commercial dietary calcium supplements are typically made from naturalsources of calcium carbonate, including limestone and oyster shell.Since calcium carbonate contains only 40% by weight of elementalcalcium, approximately 2.5 to 3.5 g of calcium carbonate must beconsumed daily to meet the recommendations. It is not practical to maketablets containing such large amounts of calcium carbonate.Consequently, supplemental calcium regimens typically compriseadministering two tablets daily of 500 to 600 mg of calcium. However,even at these calcium doses, most calcium tablets are very large anddifficult or uncomfortable to swallow. This problem is exacerbated whenexcipients are also present in the formulation. As with any solid dosepharmaceutical or nutraceutical, large tablet size often leads to poorpatient compliance. In addition to calcium supplements, thisdisadvantage is commonly encountered with tablets having large amountsof active ingredients, such as multi-vitamins and high-dosepharmaceuticals.

Prior approaches for reducing tablet size include increasing thecompaction pressure during tableting and reducing the dose of some orall of the active ingredients in a tablet. There are disadvantagesassociated with both of these approaches. For instance, high compactionpressures during tableting may result in brittle tablets that are proneto breaking. Further, disintegration and dissolution characteristics oftablets may be affected by compaction pressure, altering thebioavailablity of the active ingredient. Reducing the quantity of one ormore active ingredients per tablet requires more tablets to be consumedto achieve a required dosage or, as in the case of some multi-vitamins,results in deficiencies of selected active ingredients. For example,most commercial multi-vitamin tablets provide only 10 to 20% of theUSRDA recommended dose calcium. It is necessary to reduce the levels ofcalcium in these tablets in order to accommodate higher levels of othervitamins.

Calcium carbonate tablets, like other pharmaceutical and nutraceuticaltablets, are prepared by the application of pressure to solidformulations. Some powdered formulations inherently possess thenecessary cohesive and flow properties required for compression. Likemost powders, however, calcium carbonate lacks the ability to bedirectly compressed and must be converted into a form more suitable fortableting through a process known as granulation.

Generally, the granulation process involves treating dry powders withagents that increase the adhesive properties of the particles resultingin stable agglomerations of the powder particles. Granulation methodsknown in the art include wet granulation, dry granulation, and fluid bedgranulation. Of these, wet granulation is the most widely used method.In wet granulation, the dry powder components are blended in a suitablemixer followed by addition of a binding agent and further mixing toachieve the desired consistency. After drying, the granulatedcompositions typically have a free flowing, sand-like texture.Granulation provides the required cohesiveness and compactability forcompression into tablets of satisfactory hardness and friability.

There is a continuing need for granulations that are highly compactable.Accordingly, it is an object of the invention to provide granulationsthat can be compressed into smaller tablets than those known heretofore.Further, it is an object of the invention to provide formulations andprocesses for preparing granulations.

SUMMARY OF THE INVENTION

In accordance with the foregoing objectives, highly compactablegranulations and methods for preparing highly compactable granulationsare provided. When compressed into tablets, these granulations providetablets having small sizes or volumes heretofore not achievable in theart. In the preferred practice of the present invention, calciumcarbonate granulations are provided. While the following embodiments andexamples relate to the preferred calcium carbonate granulations, itshould be understood that the methods of the present invention would beuseful for granulation of any powdered material. Accordingly, anygranulation made according to the methods or formulations disclosedherein is contemplated to be within the scope of the present invention.

It has surprisingly been found that highly compactable calcium carbonategranulations are provided by mixing a composition comprising calciumcarbonate in a mixer capable of creating high shear and drying thecomposition in a convection drying oven. Additional improvements incompactability are obtained by employing formulations comprisingpowdered compositions of small median particle size. Furtherimprovements are obtained by employing formulations comprising two ormore powdered compositions of differing median particle size. While thebenefits of the present invention are most filly realized when theseformulations are used in conjunction with the granulation process of thepresent invention, the invention is not so limited. It is contemplatedthat the present formulations will provide improved granulations whenused in conjunction with any prior art granulation processes.

In one aspect of the present invention, granulations are providedcomprising powdered materials having a median particle diameter of about0.1 to about 20 micrometers (“μm”). Preferred granulations according tothis embodiment have median particle diameters of about 1 to about 15μm.

In another aspect of the present invention, granulated compositionscomprising a first calcium carbonate composition having a medianparticle diameter from about 10 to about 25 μm and a second calciumcarbonate composition having a median particle diameter from about 0.1to about 10 μm are provided. In a preferred embodiment, the firstcalcium carbonate composition has a median particle diameter from about12 to about 17 μm and the second calcium carbonate composition has amedian particle diameter from about 1 to about 5 μm.

In another aspect of the invention, granulated compositions comprising afirst calcium carbonate composition having a median particle diameterfrom about 10 to about 25 μm; a second calcium carbonate compositionhaving a median particle diameter from about 1 to about 10 μm; and athird calcium carbonate composition having a median particle diameterfrom about 0.1 to about 1 μm are provided.

Yet another aspect of the present invention provides a granulationprocess comprising the steps of mixing a powdered composition in a mixercapable of creating high shear and drying the composition in aconvection oven. A preferred embodiment of the process according to thisaspect of the invention comprises the steps of: (1) mixing powderedcalcium carbonate, maltodextrin and optionally additional excipients ina mixer capable of creating high shear; (2) adding water to thecomposition and mixing; (3) adding oil to the composition and mixing;and (4) drying the resulting composition in a convection drying oven.

An additional aspect of the invention provides high density calciumcarbonate granulations. In this regard, granulated calcium carbonatecompositions having an average tap density between about 0.9 and about2.0 g/cm³ are provided. Preferred granulated calcium carbonatecompositions are provided having an average tap density between about1.1 and about 2.0 g/cm³. The most preferred granulated calcium carbonatecompositions according to the invention have tap densities greater than1.3 g/cm³.

A further aspect of the invention provides tablets comprising thedisclosed granulations. Tablets prepared from the granulations of theinvention have densities about 20% to about 35% greater thancommercially available calcium supplement tablets. Accordingly, thevolume of the tablets prepared from the granulations of the invention isabout 20% to about 35% less than the volume of commercially availablecalcium supplement tablets.

These and other aspects of the invention may be more clearly understoodby reference to the following detailed description of the invention andthe appended claims.

DETAILED DESCRIPTION OF THE INVENTION

In the following description of the invention, it is to be understoodthat the terms used have their ordinary and accustomed meanings in theart, unless otherwise specified. As used herein, the term “granulation”refers to free-flowing compositions having sufficient cohesiveproperties for compression into tablets. The term “granulation process”includes, but is not limited to those processes known in the art as wetgranulation, dry granulation, fluid-bed granulation, agglomeration andspheronization.

1. Granulation Compositions.

One aspect of the present invention provides highly dense and highlycompactable granulation compositions. In the preferred practice of theinvention, the granulation compositions comprise calcium carbonate.

It is well known in the art that calcium carbonate powders having avariety of median particle diameters are commercially available. Forexample, food grade and USP grade calcium carbonate powders havingmedian particle diameters ranging from 0.7 to 20 μm are available fromsuppliers such as OMYA, Inc. (Alpharetta, Ga.), J.M Huber Corp.(Atlanta, Ga.), and Minerals Technologies Inc. (New York, N.Y.).

As shown in Table 1, calcium carbonate powders having larger medianparticle diameters provide more dense compositions when directlycompressed than calcium carbonate powders having smaller median particlediameters.

TABLE 1 Median Packed Median Packed Calcium Diameter Density CalciumDiameter Density Product¹ (μm) (g/cm³) Product² (μm) (g/cm³) OMYA-CalFG-4 AZ 3.5 1.10 HuberCAL ® 150FG 4 1.2 OMYA-Cal FG-6 AZ 6.0 1.20HuberCAL ® 250FG 6 1.3 OMYA-Cal FG-10 AZ 12 1.50 HuberCAL ® 500FG 12 1.5OMYA-Cal FG-15 AZ 15 1.55 HuberCAL ® 850FG 20 1.6 ¹Available from OMYA,Inc.; ²Available from J. M Huber Corp.

Based on the relationship between particle size and density, the skilledartisan would be motivated to select calcium carbonate powders of largemedian particle size in attempts to provide highly dense and highlycompactable granulations. It has surprisingly been found, however, thatgranulated compositions comprising small median particle size calciumcarbonate powders, which alone have relatively low pack densities,possess improved compactability as compared to granulated compositionsconsisting of larger median particle size calcium carbonate powders.Accordingly, granulated compositions comprising small median particlesize calcium carbonate powders provide unexpectedly small tablets uponcompression.

In one embodiment of the present invention, calcium carbonategranulations are provided comprising powdered calcium carbonate having amedian particle diameter of about 0.1 to about 20 μm. Within this range,exemplary granulations comprise calcium carbonate having median particlediameters of about 3.5, 6, and 12 μm. In a preferred embodiment, thegranulated compositions comprise calcium carbonate having a medianparticle diameter between about 10 and about 12 μm. The granulatedcompositions of the invention may further comprise other ingredientsincluding but not limited to maltodextrin, gum acacia, oil and water.

In the practice of the invention, it has been found desirable to employpowdered compositions having narrow particle diameter distributionsabout the mean. It will be recognized that the term “narrow particlediameter distributions” cannot generally be quantified since thevariance in particle size is related to the median particle diameter ofa powder. Additionally, manufacturing limitations associated with eachmedian particle size powder affect the distribution about the mean. Itis within the skill in the art to select powders with narrow medianparticle sizes.

As used herein, calcium carbonate powders having a median particle sizeof 15 μm have narrow particle diameter distributions if about 65% ormore of the bulk volume of the powder has a particle size between 5 and25 μm (±66% from the median) and about 40% or more of the bulk volumehas a particle size between about 10 and 20 μm (±33% from the median).Similarly, calcium carbonate powders having a median particle size of 12μm have narrow particle diameter distributions if about 50% or more ofthe bulk volume of the powder has a particle size between 4 and 20 μm(±66% from the median) and about 30% or more of the bulk volume has aparticle size between about 8 and 16 μm (±33% from the median). Calciumcarbonate powders having a median particle size of 6 μm have narrowparticle diameter distributions if about 55% or more of the bulk volumeof the powder has a particle size between 2 and 10 μm (±66% from themedian) and about 25% or more of the bulk volume has a particle sizebetween about 4 and 8 μm (±33% from the median). Calcium carbonatepowders having a median particle size of 3-4 μm have narrow particlediameter distributions if about 50% or more of the bulk volume of thepowder has a particle size between 1.2 and 5.8 μm (±66% from the median)and about 25% or more of the bulk volume has a particle size betweenabout 2.3 and 4.7 μm (±33% from the median). Suitable calcium carbonatepowders with narrow particle diameter distributions include, but are notlimited to those available from OMYA, Inc. under the trademarks OMYA-CalFG 15, OMYA-Cal USP 15, OMYA-Cal LL OC FG 15 BTH, OMYA-Cal LL USP 15,OMYA-Cal LL USP 15 BTH, OMYA-Cal FG-10AZ, OMYA-Cal FG-6AZ, and OMYA-CalUSP-4AZ.

While the preferred powders have narrow median particle sizedistributions it will be understood that any powder is contemplated asbeing useful with the present invention. For example, 12 μm medianparticle size calcium carbonate powders having a distribution about themedian broader than described above provide granulations superior incompactability to those of the prior art.

In the practice of the invention, it has also been found useful toemploy small median particle size powders in combination with largermedian particle size powders. In one embodiment of the invention, thegranulation compositions comprise a first powdered composition having amedian particle diameter from about 10 to about 25 μm and a secondpowdered composition having a median particle diameter from about 0.1 toabout 10 μm.

The first and second powdered compositions may be any powdered material.Preferably, the first and second powdered compositions are materialsused in the formulation of pharmaceutical and nutraceutical tablets,including active ingredients and excipients. Examples of powderedmaterials and excipients contemplated to be useful according to thepresent invention include but are not limited to calcium carbonate,dicalcium phosphate, calcium sulfate, ferrous sulfate and other ironcompounds, lactose, cellulose, micro-crystalline cellulose (Avicel),kaolin, mannitol, maltodextrin, oil, sodium chloride, starch, powderedsugar, talc (magnesium silicate hydroxide), and silica. In the preferredpractice of the invention the first and second powdered compositions arecalcium carbonate.

In a preferred embodiment of the invention, the first powderedcomposition comprises calcium carbonate having a median particlediameter of about 12 to about 17 μm and the second powdered compositioncomprises calcium carbonate having a median particle diameter of about 1to about 5 μm. In a more preferred embodiment of the invention, thefirst powdered composition comprises calcium carbonate having a medianparticle diameter of about 15 μm and the second powdered compositioncomprises calcium carbonate having a median particle diameter of about 4μm.

The first and second powdered compositions may each comprise any weight% of the granulated composition. In a preferred embodiment, the firstpowdered composition comprises from about 50 to about 100 weight % ofthe granulated composition and the second powdered composition comprisesfrom about 0 to about 50 weight % of the granulated composition. In amore preferred embodiment, the first powdered composition comprises fromabout 60 to about 80 weight % of the granulated composition and thesecond powdered composition comprises from about 20 to about 40 weight %of the granulated composition. In the most preferred embodiment, thefirst powdered composition comprises about 70 weight % of the granulatedcomposition and the second powdered composition comprises about 30weight % of the granulated composition.

It will be understood that the first and second powdered compositionsaccording to the invention are not necessarily the same chemicalcompound. For instance, it is contemplated that the first powderedcomposition may be an excipient and the second powdered composition maybe an active ingredient, or vice versa. In one embodiment of theinvention, the first powdered composition is calcium carbonate and thesecond powdered composition is talc.

Another granulated composition according to the present inventioncomprises a first powdered composition having a median particle diameterfrom about 10 to about 20 μm, a second powdered composition having amedian particle diameter from about 1 to about 10 μm, and a thirdpowdered composition having a median particle diameter from about 0.1 toabout 1 μm. The first, second, and third powdered compositions may eachcomprise any weight % of granulated composition. In a preferredembodiment, the granulated composition comprises from about 60 to about80 weight % of the first powdered composition, from about 20 to about 40weight % of the second powdered composition, and from about 0.5 to about5 weight % of the third powdered composition.

The first, second and third powdered compositions may be independentlyselected from any powdered material. In a preferred embodiment, at leastone of the first, second, and third powdered compositions is calciumcarbonate. In a more preferred embodiment, each of the first, second,and third powdered compositions are calcium carbonate.

The granulated compositions of the present invention may comprise othermaterials in addition to the powdered compositions described above. Forexample, it may be desirable to add excipients to the granulation toimpart certain physical characteristics to the granulation or resultingtablets. Excipients that may be used with the present invention include,but are not limited to diluents, binders, glidants, lubricants,disintegrants, colors, flavors, sweeteners, and solubility retardingagents. Preferred excipients according to the invention are maltodextrinand oil. When present, the granulated compositions preferably comprisebetween about 2 and about 10 weight % maltodextrin and about 0.1 toabout 1 weight % oil.

It is contemplated that any oil or oil-like material compatible with apharmaceutical or nutraceutical product will be useful according to theinvention. Preferred oils are canola oil, mineral oil, coconut oil,cotton seed oil, rape seed oil, sunflower seed oil, palm oil, vegetableoil and soy oil. Mineral oil is the most preferred oil according to theinvention.

The formulations may further comprise one or more hydrocolloids. Anyhydrocolloid that is compatible with a pharmaceutical or nutraceuticalproduct may be used in the granulations of the invention. Preferredhydrocolloids are selected from vegetable gums, including but notlimited to alginates, carrageenan, dextran, furcellaran, pectin,gelatin, gum agar, locust bean gum, gum ghatti, guar gum, gumtragacanth, acacia, gum arabic, xanthan gum, karaya gum, tara gum,cellulose derivatives, starch derivatives, and combinations thereof. Onevegetable gum that has been found to be particularly useful is gumacacia.

The granulated calcium carbonate compositions of the present inventionhave a free-flowing quality and a dense, sand-like texture. Preferredgranulations have an average tap density between about 0.9 and about 2.0g/cm³ as measured using a Van Kel bulk and tap density gauge. Morepreferably, the granulated compositions have an average density betweenabout 1.1 and about 2.0 g/cm³. Most preferred granulated compositionsaccording to the invention have an average density between about 1.3 andabout 2.0 g/cm³.

2. Granulation Process.

Another aspect of the present invention provides a process for preparinghighly dense and highly compressible granulation compositions.

The granulation process of the present invention comprises the steps of:(1) mixing a powdered material and optionally additional ingredientssuch as excipients in a mixer capable of creating high shear; and (2)drying the resulting composition in a convection drying oven.

A preferred embodiment of the process comprises the steps of: (1) mixingpowdered calcium carbonate, maltodextrin and optionally additionalexcipients in a mixer capable of creating high shear; (2) adding waterto the composition and mixing therewith; (3) adding oil to thecomposition and mixing therewith; (4) drying the resulting compositionin a convection drying oven. The amount of calcium carbonate,maltodextrin, and oil are determined according the proportions describedabove. The amount of water added will preferably be between about 5 andabout 20 weight % based on the amount of calcium carbonate. However, theamount of water may be more or less depending on the desired density andtexture of the granulation. In the practice of the invention it has beenfound desirable to use hot water or steam. Preferably, the water isheated to about 93° C. or greater before it is mixed with the calciumcarbonate. After the composition is mixed with water, the compositionwill preferably reach a temperature of about 45° C. to about 50° C.

A more preferred embodiment of the process comprises the steps of: (1)mixing at least two powdered calcium carbonate compositions havingdiffering median particle size distribution, as described above, withmaltodextrin and optionally additional excipients in a mixer capable ofcreating high shear; (2) mixing for about 60 seconds at mixer speedsfrom about 200 rpm to about 300 rpm; (3) adding an amount of hot wateror steam comprising from about 5 to about 20 weight % based on the totalamount of calcium carbonate composition; (4) mixing for about 6 minutes;(5) adding oil or oil-like material to the composition and mixingtherewith; and (6) drying the resulting composition in a convectiondrying oven.

While the granulated compositions may be dried by any method known inthe art, the compositions are preferably dried in a convection oven.Examples of convection drying ovens include, but are not limited to,tray dryers, vertical fluidized bed ovens, horizontal fluidized bedovens, spray dryers, and impingement ovens. It has been found useful toadjust the oven conditions to yield a final composition having a watercontent of less than approximately 1% by weight. In the preferredpractice of the invention, the composition is heated to between about50° C. to about 150° C. in the oven.

It will be understood that the mixing times described above will varysomewhat depending on factors such as the total quantity of materials tobe mixed, the speed of the mixer, and the design of the impeller blades.It is within the skill in the art to optimize the mixing times toachieve the desired texture and density of the resulting granulation.

It is contemplated that any mixer which provides high shear may beemployed in the process, including but not limited to Hobart mixers andthose mixers known in the art as “high shear” mixers.

It will be understood that the processes described herein have generalapplicability for preparing highly dense and highly compressiblegranulated compositions and are not limited to granulating theformulations described above. Similarly, it is contemplated that theformulations described herein will provide improved granulatedcompositions when employed in any granulation process known in the art,including but not limited to fluidized bed granulation processes.

The granulations disclosed herein are useful for preparingpharmaceutical and nutraceutical tablets. Tablets according to thepresent invention include but are not limited to molded tablets,chewable tablets, pellets, pills, triturates, hypodermic tablets,effervescent tablets, controlled-release tablets, and immediate releasetablets. Tablets prepared from the granulations of the invention havedensities about 20% to at least about 35% greater than commerciallyavailable calcium supplement tablets. Accordingly, the volume of thetablets prepared from the granulations of the invention is about 20% toat lest about 35% less than the volume of commercially available calciumsupplement tablets.

EXAMPLE I

A granulated calcium carbonate composition was prepared from calciumcarbonate having a median particle diameter of about 6 μm using theprocess of the present invention. The ingredients for this formulationare listed in Table 2.

TABLE 2 Ingredient Weight Kg OMYA-CAL FG-6AZ¹ 22.70 MaltrinM100/Maltodextrin² 1.20 Drakeol 34/Mineral Oil³ 0.24 Purified Water 3.00¹OMYA, Inc.; ²Grain Processing Corp.; ³Penreco.

The bowl of a Collette Gral Model 600 high shear mixer was charged withcalcium carbonate (OMYA-CAL FG-6AZ) and maltodextrin (Maltrin M100) inthe amounts shown in Table I. These ingredients were mixed for 60seconds at mixer speed from about 200 to about 300 rpm. Purified waterheated to approximately 93° C. was then added to the mixture through awater line. The composition was mixed until steam stopped being producedfrom the composition (approximately six minutes). Mineral oil was thensprayed onto the composition using a spray nozzle fed by a line throughthe head of the mixer. The composition was mixed for approximately oneminute.

The mixing bowl was then lowered and the composition was collected in aplastic bag. The composition was then poured through a transition funnelinto a vibratory feeder which deposited the charge onto a belt conveyor.The belt conveyor conveyed the composition onto a weigh belt thatmetered the composition uniformly into a Carrier model QAD/C 1260 Shorizontal fluidized bed convection oven. The oven temperature wascontrolled to produce a product temperature of about 100° C. to about150° C. The composition exiting the terminal end of the oven had amoisture content of less than about 1% by weight.

The dry composition was screened using an 18×18 U.S. mesh screen and theparticles passing therethrough were collected as a first batch. Theoversize particles remaining on the screen were collected and passedthrough a Crack-U-Lator roll granulator in order to reduce the size ofoversized particles. The discharge from the Crack-U-Lator was thenpassed through an 18×18 U.S. mesh screen and combined with the firstbatch.

The granulated composition was free flowing and had a sand-like texture.The composition had an improved mouth-feel and reduced “chalkiness” ascompared to powdered calcium carbonate.

The tap density of the resulting dry granulation was measured using aVan Kel Bulk and Tap Density Gauge. The tap density of the calciumcarbonate granulation was greater than or equal to about 1.1 g/cm³.Tablets containing 600 mg of calcium carbonate prepared from thisgranulation were about 20% smaller in volume than commercially available600 mg Caltrate® tablets.

EXAMPLE II

To further investigate the effect of median particle diameter ongranulation density, a granulated composition was prepared from calciumcarbonate powder having a median particle diameter of about 12 μm(OMYA-CAL FG-10AZ ) using the process of the present invention. Theingredients for this formulation are listed in Table 3.

TABLE 3 Ingredient Weight Kg OMYA-CAL FG-10AZ¹ 22.70 MaltrinM100/Maltodextrin² 1.20 Drakeol 34/Mineral Oil³ 0.24 Purified Water 3.00¹OMYA, Inc.; ²Grain Processing Corp.; ³Penreco.

The granulation process was identical to the process described inExample 1.

The tap density of the resulting dry granulation was measured using aVan Kel Bulk and Tap Density Gauge. The tap density of the calciumcarbonate granulation was greater than or equal to about 1.0 g/cm³.Tablets containing 600 mg of calcium carbonate prepared from thisgranulation were about 20% smaller in volume than commercially available600 mg Caltrate® tablets.

EXAMPLE III

A granulated composition was prepared from calcium carbonate having amedian particle diameter of about 15 μm (Calcium Carbonate LL USP 15,OMYA, Inc.) using the process of the present invention. The ingredientsfor this formulation are listed in Table 4.

TABLE 4 Ingredient Weight % Calcium Carbonate LL USP 15¹ 93.21 MaltrinM-180/Maltodextrin² 6.58 Drakoel 34/Mineral Oil³ 0.205 HydroxypropylMethylcellulose⁴ 0.001 Stearic Acid 0.001 Polyplasdone XL/Crospovidone⁵0.001 Magnesium Stearate 0.001 ¹OMYA, Inc; ²Grain Processing Corp.;³Penreco; ⁴Dow Chemical Co.; ⁵International Specialty Products, Inc,

The granulation process was identical to the process described inExample 1.

The tap density of the resulting dry granulation was measured using aVan Kel Bulk and Tap Density Gauge. The tap density of the calciumcarbonate granulation was greater than or equal to about 1.0 g/cm³.Tablets containing 600 mg of calcium carbonate prepared from thisgranulation were about 20% smaller in volume than commercially available600 mg Caltrate® tablets.

EXAMPLE IV

This example illustrates the improvement in density that is achieved byemploying a formulation comprising two calcium carbonate compositionshaving differing median particle diameters in the process of the presentinvention. As shown in Table 5, the composition comprises a 50:50 weightratio of calcium carbonate having a median particle diameter of about 15μm (Cal Carb OC USP PDR) and calcium carbonate having a median particlediameter of about 6 μm (OMYA-CAL FG-6AZ).

TABLE 5 Ingredient Weight Kg OMYA-CAL FG-6AZ¹ 11.35 Cal Carb OC USP PDR¹11.35 Maltrin M100/Maltodextrin² 1.20 Drakeol 34/Mineral Oil³ 0.24Purified Water 3.00 ¹OMYA, Inc.; ²Grain Processing Corp.; ³Penreco.

The granulation process was identical to the process described inExample 1.

The tap density of the resulting dry granulation was measured using aVan Kel Bulk and Tap Density Gauge. The tap density of the calciumcarbonate granulation was greater than or equal to about 1.1 g/cm³.Tablets containing 600 mg of calcium carbonate prepared from thisgranulation were about 20% smaller in volume than commercially available600 mg Caltrate® tablets.

EXAMPLE V

This Example provides a granulated composition comprising a 70:30 weightratio of calcium carbonate having a median particle diameter of about 15μm (Cal Carb OC USP PDR) and calcium carbonate having a median particlediameter of about 4 μm (OMYA-CAL USP-4AZ).

TABLE 6 Ingredient Weight Kg OMYA-CAL USP-4AZ¹ 6.80 Cal Carb OC USP PDR¹15.9 Maltrin M100/Maltodextrin² 1.20 Drakeol 34/Mineral Oil³ 0.24Purified Water 3.00 ¹OMYA, Inc.; ²Grain Processing Corp.; ³Penreco.

The granulation process was identical to the process described inExample 1.

The bulk density of the granulation was about 0.9 g/cm³. The tap densityof the resulting dry granulation was measured using a Van Kel Bulk andTap Density Gauge. The tap density of the calcium carbonate granulationwas greater than or equal to about 1.1 g/cm³. Tablets containing 600 mgof calcium carbonate prepared from this granulation were about 20%smaller in volume than commercially available 600 mg Caltrate® tablets.

EXAMPLE VI

This Example provides a granulated composition comprising calciumcarbonate having a median particle diameter of about 10 μm with a broadparticle size distribution about the median.

TABLE 7 Ingredient Weight % Calcium Carbonate OC-10¹ 94.04 MaltrinM100/Maltodextrin² 4.97 Drakeol 34/Mineral Oil³ 0.99 ¹OMYA, Inc.; ²GrainProcessing Corp.; ³Penreco.

The granulation process was identical to the process described inExample 1, with an amount of hot water equal to about 10% by weightbased on the weight of calcium carbonate added during mixing.

The tap density of the resulting dry granulation was measured using aVan Kel Bulk and Tap Density Gauge. The tap density of the calciumcarbonate granulation was between about 1.25 and 1.31 g/cm³. Tabletscontaining 600 mg of calcium carbonate prepared from this granulationwere about 20% smaller in volume than commercially available 600 mgCaltrate® tablets.

The invention having been described by the foregoing description of thepreferred embodiments, it will be understood that the skilled artisanmay make modifications and variations of these embodiments withoutdeparting from the spirit or scope of the invention as set forth in thefollowing claims.

1. A wet granulation process for preparing calcium carbonate granulationcomprising the steps of: (1) mixing in a high shear mixer a compositioncomprising powdered calcium carbonate having a median particle diameterfrom 6 μm to 12 μm, maltodextrin and optionally additional excipients;(2) adding water to the composition in an amount from about 5 to about20% by weight based on the amount of calcium carbonate and mixingtherewith; (3) adding oil to the composition and mixing therewith; and(4) drying the resulting composition by convection drying in ahorizontal fluidized bed oven to thereby provide a calcium carbonategranulation.
 2. The process according to claim 1, wherein said calciumcarbonate powder has a median particle size of 12 μm.
 3. The processaccording to claim 1, wherein said granulation has a tap density betweenabout 1.0 and about 2.0 g/cm³.
 4. The process according to claim 2,wherein said granulation has a tap density between about 1.1 and about2.0 g/cm³.
 5. The process according to claim 1, wherein saidmaltodextrin comprises from about 2% to about 10% by weight of saidgranulation.
 6. The process according to claim 2, wherein said oilcomprises from about 0.1% to about 1% by weight of said granulation. 7.The process according to claim 1, further comprising one or moreexcipients selected from the group consisting of diluents, binders,glidants, lubricants, disintegrants, colors, flavors, sweeteners,solubility retarding agents, and combinations thereof.
 8. The processaccording to claim 1, wherein said granulation has a water content ofless than about 1% by weight.
 9. The process according to claim 2,wherein said calcium carbonate powder has a particle size distributionwherein at least 50% of the bulk volume of the powder has a particlesize between 4 and 20 μm and at least 30% of the bulk volume of thepowder has a particle size between 8 and 16 μm.
 10. The processaccording to claim 2, wherein said calcium Carbonate powder has aparticle size distribution broader than a distribution wherein at least50% or more of the bulk volume of the powder has a particle size between4 and 20 μm and at least 30% of the bulk volume of the powder has aparticle size between 8 and 16 μm.